1. Field of the Invention
The invention relates to laminates containing substance for transdermal systems.
2. Description of the Related Art
The treatment of chronic diseases by administration of highly active drugs is a recognized method of treatment well accepted by patients. In particular, the treatment of hormone deficiencies with estrogens or testosterone, besides the administration of strong analgesics, is a rapidly growing segment of the pharmaceutical market.
A problem common to all transdermal forms of administration is the need to overcome the diffusion barrier of the skin and to maintain therapeutically effective blood levels.
Transdermal systems such as active substance-containing adhesives, bandages and the like are often used as are creams and ointments. These systems, sold in different technical embodiments such as matrix systems or reservoir systems, are well known to those skilled in the art of transdermal administration of active substances. In general, reservoir systems contain solutions of active pharmaceutical substances in a liquid, highly volatile solvent such as ethanol, capable of increasing permeation through the intact skin. By contrast, the drug-in-adhesive or matrix systems do not employ these volatile solvents. Instead, they use absorption enhancers that are soluble in the matrix and do not volatilize during the preparation process.
Absorption accelerators for matrix systems are typically lipophilic, low-volatile liquids, such as fatty esters, medium- or long-chain alcohols, emulsifiers, terpenes and the like. Their action is based on the following essential mechanisms:    a) they disturb the diffusion-hindering structures of the lipid double-layers of the stratum corneum, or    b) they increase the concentrations/saturation concentrations of the drugs in the stratum corneum.
As a result, both mechanisms increase the flux of the active substance through the skin. Particularly when the make-up of the skin structures is disturbed or destroyed, to improve permeation, the skin reacts with undesirable side effects such as reddening, itching, inflammation and the like. In severe cases, allergic reactions can occur. Only very few commercially available transdermal systems contain no absorption accelerators. The basis for diffusion through membranes—such as the skin—are Fick's diffusion laws. According to these laws, permeation through membranes is determined by the concentration gradient of the diffusing substance along the cross-section of the membrane. The gradient is created by the difference in concentration of the active substance between the donor compartment (transdermal system) and the skin. For simplicity, the skin in this case is assumed to be an ideal homogeneous membrane. Hence, skin permeation can be modified by, among other things, varying the active substance concentrations in transdermal systems. The increase in skin permeation, needed in a great majority of cases, is limited by a) the saturation solubility of the drug involved in the adhesive-active substance solution used to prepare the transdermal system or b) the saturation solubility in the adhesive matrix.
In the following, the two cases are described separately.
A) In the predominant number of cases, the drugs are either dissolved in the solutions of the adhesives in organic solvents such as ethyl acetate, acetone, hexane or heptane directly or with the addition of compatible solvents. The amount of solvent that can be added to the adhesive solutions to be able to predissolve the active substances therein is limited by the compatibility with the adhesive solutions involved or by the resulting dilution of the adhesive solids content. In practice, the coating methods known to those skilled in the art make it possible to process only adhesive solutions with a defined minimum viscosity and solids content. Nonpolar solvents, in particular, which are used for processing nonpolar polymers such as polyisobutylene, have only slight dissolution power for active substances such as sex hormones, antihypertensive agents, analgesics etc. As a rule, the dissolution power is not sufficient to produce adhesive matrices with optimum active substance loading after the solvent has evaporated. Even in acrylate adhesives, which are mainly processed from ethyl acetate-containing solvent mixtures, the dissolution power is not sufficient to dissolve, for example, derivatives of sex hormones, such as ethinylestradiol, levonorgestrel and the like in quantities that would be necessary to produce a sufficient concentration gradient between the transdermal system and the skin.
B) In practice, if sufficient concentrations of the active substance can be achieved, supersaturated and thus metastable conditions of the embedded active substances very often arise in the dried matrix. The drugs in such metastable matrices tend to recrystallize on storage, such crystallization resulting in a decrease in active substance concentration and thus in a decrease of the concentration gradient. Moreover, the adhesive properties of the recrystallized matrix can change to become very unfavorable, in some cases rendering the matrix unusable. Even polymers with a very high dissolution power cannot dissolve, for example, more than 2.5-3% of sex hormones in a stable manner. Permeation experiments with highly supersa-turated adhesive matrices have shown that the skin allows higher quantities of hormones to permeate than stable saturated or unsaturated transdermal systems permit. Thus, the limiting step is not the permeation capacity of the skin but the active substance loading of the stable matrices.
To prevent the use of—potentially—harmful absorption enhancers in transdermal systems and to realize high flow rates that will result in reliable blood levels, a technology is needed which will permit the production of transdermal systems with high active substance loading and good storage stability.
It is known from the prior art to embed an active substance in a polymer for the purpose of modifying and controlling its release properties. The prior-art describes the use of polymers to stabilize super-saturated conditions in transdermal systems [TDS] (J. Pharmacobio-Dyn. 10, 743, 1987). German Patent DE 4 334 553 A1 discloses increasing the flow rate by means of a supersaturated condition. On prolonged storage or prolonged duration of application, such supersaturations in energy-rich structures, however, can cause instabilities thus putting a time limit on the system's usefulness.
European Patent EP 0 516 141 A1 describes a bioadhesive pharmaceutical preparation in which active substance-bearing microunits, including embedded polymer particles, are compressed together with adhesive polymers and various other auxiliary agents and comminuted to form granules. Although this use comprises the idea of employing granular polymer inclusions independently of the adhesive component thus achieving greater flexibility in controlling active substance release after application, the technology proposed here is not suitable for the production of stable laminates for TDS in terms of either their objective or the method of preparation.
EP 0 481 443 A1 discloses the use of microporous particles or microspheres of chemically crosslinked polymers as carriers for the active substance and/or the absorption enhancer. The limited loadability of the microspheres with active substance, imparted by the preparation technology, and the use of crosslinked polymers, however, generate only a limited active substance diffusion pressure through the skin so that, here, too, it is necessary to use additional absorption enhancers. The systems described in DE 4 405 898 A1, EP 0 674 900 A1 and DE 19701949 A1 have the same drawback. These systems use the active substance together with a nonadhesive polymer which acts as crystallization retarder and to which adhesive properties are later imparted by chemical or physical mechanisms.
U.S. Pat. No. 5,656,286 describes the use of soluble polyvinyl chloride [PVC] in admixture with polyvinyl-pyrrolidone for the purpose of preventing the crystallization of the active substances, but the active substance release rate is not improved.
U.S. Pat. No. 5,702,721 describes a matrix which comprises an impermeable backing layer, a matrix with an active substance that can be activated and a layer which regulates the access of liquid. The matrix consists of a material which is permeable to water vapor but in itself is not water-soluble and contains no active substance. Included in this matrix are “islands” of water-soluble or water-swellable material loaded with active substance. The loading of unloaded islands can be achieved by solid-liquid absorption or by special drying methods. The complicated structure and process of producing this multilayer system represents a drawback. A special mechanism for regulating the access of skin moisture is needed, because otherwise the active substance precipitates or the release of active substance is insufficient.